8-K

 

 

UNITED STATES

SECURITIES AND EXCHANGE COMMISSION

WASHINGTON, D.C. 20549

 

 

FORM 8-K

 

 

CURRENT REPORT

PURSUANT TO SECTION 13 OR 15(d)

OF THE SECURITIES EXCHANGE ACT OF 1934

Date of Report (Date of earliest event reported): May 7, 2019

 

 

MODERNA, INC.

(Exact name of registrant as specified in its charter)

 

 

 

Delaware   001-38753   81-3467528
(State or other jurisdiction
of Incorporation)
  (Commission
File Number)
  (IRS Employer
Identification Number)

 

200 Technology Square
Cambridge, MA
  02139
(Address of registrant’s principal executive office)   (Zip code)

(617) 714-6500

(Registrant’s telephone number, including area code)

N/A

(Former name or former address, if changed since last report)

 

 

Check the appropriate box below if the Form 8-K filing is intended to simultaneously satisfy the filing obligation of the registrant under any of the following provisions:

 

Written communications pursuant to Rule 425 under the Securities Act (17 CFR 203.425)

 

Soliciting material pursuant to Rule 14a-12 under the Exchange Act (17 CFR 240.14a-12)

 

Pre-commencement communications pursuant to Rule 14d-2(b) under the Exchange Act (17 CFR 240.14d-2(b))

 

Pre-commencement communications pursuant to Rule 13e-4(c) under the Exchange Act (17 CFR 240.13e-4(c))

Indicate by check mark whether the registrant is an emerging growth company as defined in Rule 405 of the Securities Act of 1933 or Rule 12b-2 of the Securities Exchange Act of 1934.

Emerging growth company  ☒

If an emerging growth company, indicate by check mark if the registrant has elected not to use the extended transition period for complying with any new or revised financial accounting standards provided pursuant to Section 13(a) of the Exchange Act. ☐

Securities registered pursuant to Section 12(b) of the Act:

 

Title of each class

 

Trading symbol(s)

 

Name of each exchange

on which registered

Common stock, par value $0.0001

per share

  MRNA   The NASDAQ Stock Market LLC

 

 

 


Item 7.01 Regulation FD Disclosure

As previously announced, Moderna, Inc. (the “Company”) will give a live webcast today, May 7, 2019, in conjunction with its 2019 Science Day and host a tour of its Norwood manufacturing facility in the afternoon. The Science Day webcast and Norwood manufacturing facility tour will include slide presentations, excerpts of which are attached as Exhibits 99.1 and 99.2, respectively, to this Current Report on Form 8-K and are incorporated by reference in this Item 7.01.

The Science Day webcast will be available on the Company’s website for at least 30 days following the event. The information contained on the Company’s website is not part of this Form 8-K and is not incorporated by reference into this Form 8-K.

The information in this Item 7.01 to this Current Report on Form 8-K, and in Exhibits 99.1 and 99.2 furnished herewith, shall not be deemed to be “filed” for purposes of Section 18 of the Securities Exchange Act of 1934, as amended (the “Exchange Act”), or otherwise subject to the liabilities of that section, nor shall such information be deemed incorporated by reference in any filing under the Securities Act of 1933, as amended, or the Exchange Act, except as expressly set forth by specific reference in such a filing.

Item 9.01. Financial Statements and Exhibits.

(d) Exhibits.

 

Exhibit
No.

  

Description

99.1    Slide presentation to be presented at the Moderna, Inc. 2019 Science Day on May 7, 2019
99.2    Slide presentation to be presented at a tour of Moderna, Inc.’s Norwood manufacturing facility on May 7, 2019


SIGNATURES

Pursuant to the requirements of the Securities Exchange Act of 1934, the registrant has duly caused this report to be signed on its behalf by the undersigned hereunto duly authorized.

 

Date: May 7, 2019     MODERNA, INC.
    By:   /s/ Lori Henderson
      Lori Henderson
      General Counsel and Corporate Secretary
EX-99.1

Slide 1

Scientific Symposium May 7, 2019 Confidential and Proprietary ·  © 2018 Moderna Therapeutics Exhibit 99.1


Slide 2

Confidential and Proprietary ·  © 2018 Moderna Therapeutics Forward-looking statements This presentation contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995, as amended. In some cases, forward-looking statements can be identified by terminology such as “will,” “may,” “should,” “expects,” “intends,” “plans,” “aims,” “anticipates,” “beliefs,” “estimates,” “predicts,” “potential,” “continue,” or the negative of these terms or other comparable terminology, although not all forward-looking statements contain these words. The forward-looking statements in this presentation are neither promises nor guarantees, and you should not place undue reliance on these forward-looking statements because they involve known and unknown risks, uncertainties and other factors, many of which are beyond Moderna’s control and which could cause actual results to differ materially from those expressed or implied by these forward-looking statements. These risks, uncertainties and other factors include those described in Moderna’s most recent Annual Report on Form 10-K filed with the U.S. Securities and Exchange Commission (SEC) and in subsequent filings made by Moderna with the SEC, which are available on the SEC's website at www.sec.gov. Except as required by law, Moderna disclaims any intention or responsibility for updating or revising any forward-looking statements in this presentation in the event of new information, future developments or otherwise. These forward-looking statements are based on Moderna’s current expectations and speak only as of the date hereof.


Slide 3

Welcome Stéphane Bancel Chief Executive Officer


Slide 4

Large product opportunity Higher probability of technical success Accelerated research and development timelines Greater capital efficiency over time vs. recombinant technology mRNA as a potential new class of medicines


Slide 5

Moderna’s Mission Deliver on the promise of mRNA science to create a new generation of transformative medicines for patients. Slide


Slide 6

Confidential and Proprietary ·  © 2018 Moderna Therapeutics mRNA sciences has dozen of vectors


Slide 7

Our commitment to be the best at mRNA science is core to who we are Product Performance 2011 Inception Time 2019 © 2018 Moderna Therapeutics Investing: For the long-term & At scale


Slide 8

Our commitment to be the best at mRNA science is core to who we are Product Performance 2011 Inception Time 2019 © 2018 Moderna Therapeutics Capturing future product performance improvements requires investments 1) for the long-term 2) at scale 3) with the right team We have advanced mRNA science to enable our current development pipeline


Slide 1

Expanding frontiers: Introduction to the immune nanoparticle program Confidential and Proprietary ·  © 2019 Moderna Therapeutics Stephen Hoge, MD President


Slide 2

Immune system Tissue resident Waste disposal, maintenance Initiation & resolution of inflammation Many types Confidential and Proprietary ·  © 2019 Moderna Therapeutics Mucosa associated (MALT) Non-encapsulated; epithelium Defense & homeostasis Regulatory CD25 CD4 Helper CD4 Cytotoxic CD8 >90% of myeloid ~50% of lymphoid Lymph nodes ~500 in body B cell maturation T-cell priming ~30% of lymphoid Helper Cytotoxic CD4 CD8 Spleen Large lymph node for blood (priming, maturation) Cell storage and long-lived niches Maintenance of RBCs ~20% of lymphoid ~10% of myeloid CD4+ CD8+ Treg Bone marrow Hematopoiesis Cell storage and long-lived niches (plasma cells, memory, MSCs)


Slide 3

Immune system Tissue resident Waste disposal, maintenance Initiation & resolution of inflammation Many types Confidential and Proprietary ·  © 2019 Moderna Therapeutics Mucosa associated (MALT) Non-encapsulated; epithelium Defense & homeostasis Regulatory CD25 CD4 Helper CD4 Cytotoxic CD8 >90% of myeloid ~50% of lymphoid Lymph nodes ~500 in body B cell maturation T-cell priming ~30% of lymphoid Helper Cytotoxic CD4 CD8 Spleen Large lymph node for blood (priming, maturation) Cell storage and long-lived niches Maintenance of RBCs ~20% of lymphoid ~10% of myeloid CD4+ CD8+ Treg Bone marrow Hematopoiesis Cell storage and long-lived niches (plasma cells, memory, MSCs) Network of diverse cell types (1012) Interact through cell-to-cell synapses Hugely different cell composition in different locations (essential to function)


Slide 4

Identifying a lead Immune Nanoparticle Confidential and Proprietary ·  © 2019 Moderna Therapeutics


Slide 5

Policeman mRNA-based immune system therapeutics


Slide 6

Transient protein expression to reprogram cells into new functions and phenotypes Dose-dependent in vivo pharmacology to all major cell types (system) Leverage programable trafficking to ensure desired interactions mRNA software to select cell type(s) and ensure safety


Slide 7

Setting the objective Dose-dependent in vivo pharmacology to all major cell types (system) How much expression do we need (how many cells)? Healthy CMV seropositive adults can have 5-10% of their peripheral CD8+ T cell pool responsive to the virus Human cell therapies (CART) dose ~300 million T-cells (~0.8% of CD8+) T regs (CD4+CD25+FoxP3+) comprise 5–10% of CD4+T cells …5% of all major cell types (T cells, B cells, NK cells, Neutrophils, Monocytes)


Slide 8

Human PBMC Ex vivo performance of immune NP Collect multiple donors Expose to Immune NP at same concentrations achieved in blood following IV administration (100ng per 2x105 cells) Use an mRNA encoding a transmembrane reporter (e.g., mouse OX40L)


Slide 9

Human PBMC Percent of human PBMC cells expressing reporter (by type, 24h) FSC Transmembrane reporter (murine OX40L) 5%


Slide 10

Confidential and Proprietary ·  © 2019 Moderna Therapeutics T cells NKT CD1r CD3 TCR CD4 Helper Cytotoxic CD8 Regulatory CD25 CD4 28% 18% 26% 19%


Slide 11

Human PBMC T cells Does repeat dosing increase the effect?


Slide 12

Human PBMC Repeat dose pharmacology Dose 1 (24 hours) Dose 2 (48 hours) Dose 3 (72 hours) Immune NP Control T cells CD3+ Amount of protein per cell (MFI) also increases linearly Percent of human CD3+ cells expressing reporter, 24h after each dose


Slide 13

Does it translate in vivo? Administer a standard mRNA dose intravenously (0.3 mpk) using Immune NP Collect splenocytes & PBMCs at 24 hours Measure expression through FACS using transiently expressed transmembrane reporter (confirmatory imaging)


Slide 14

Mouse in vivo T cells transfected upon single IV dose Control Reporter (Immune NP) Reporter (mOX40L) positive cells among CD3+ splenocytes Reporter (Immune NP) Control C57Bl6 strain Balb/c strain Control Reporter (Immune NP) Reporter (mOX40L) positive cells among CD3+CD4+ splenocytes Reporter (Immune NP) Control C57B6 strain Balb/c strain Control Reporter (Immune NP) Reporter (mOX40L) positive cells among CD3+CD8+ splenocytes Reporter (Immune NP) Control C57B6 strain Balb/c strain CD3 CD4 Helper Cytotoxic CD8+ CD4+ T cells (all CD3+)


Slide 15

Mouse in vivo B cells transfected upon single IV dose Control Reporter (Immune NP) Reporter (mOX40L) positive cells among CD19+ splenocytes Reporter (Immune NP) Control C57Bl6 strain Balb/c strain Approximately 30% of CD19+ splenocytes express reporter 24 hours after single dose Spleen includes mature B cells and specialized populations (marginal zone B-cells and plasma cells) B cells (all CD19+)


Slide 16

Mouse in vivo Summary T cells B cells Monocytes Cell type 5% Average reporter (mOX40L) positive cells by cell type, splenocytes (n=20) Low/no staining at 24 hours in peripheral lymph nodes Lower staining in peripheral blood, particularly for lymphocytes, suggesting dilution from re-trafficking (data not shown)


Slide 17

Mouse in vivo Investigating cell trafficking Kauffman, Kevin J., et al. "Rapid, Single-Cell Analysis and Discovery of Vectored mRNA Transfection In Vivo with a loxP-Flanked tdTomato Reporter Mouse." Molecular Therapy-Nucleic Acids 10 (2018): 55-63. Immune NP with mRNA encoding for Cre recombinase In vivo gene edit results in tdTomato reporter permanently turned on Sample immune tissues at 48 hours to cell trafficking


Slide 18

Mouse in vivo Blood cell types in ROSA (Cre-Lox) mice T cells CD4+ CD8+ B cells Monocytes Eosinophils Neutrophils Granulocytes 25% 25% 24% 26% 63% 83% 18% 32% CD4 Helper Cytotoxic CD8 Percent reporter positive cells by cell type 48-hours after a single IV dose of mRNA encoding Cre recombinase in Immune NP, PBMC


Slide 19

Mouse in vivo Distribution of cells by lymphoid organ T cells B cells Myeloid (various) Cell type Blood Spleen Lymph node (inguinal) Bone marrow 25% 15% 6% 9% 26% 8% 6% 8% 63% 44% 36% 7% Percent reporter positive cells by cell type 48-hours after a single IV dose of mRNA encoding Cre recombinase in Immune NP, by tissue location


Slide 20

NHP in vivo T cells (all) 12% of T cells in vivo Buffer Control mRNA (Immune NP) Reporter mRNA (Immune NP) Reporter (mOX40L) positive cells among CD3+ splenocytes 24 hours post-dose, transmembrane reporter


Slide 21

NHP in vivo B cells 13% of B cells in vivo Buffer Control mRNA (Immune NP) Reporter (mOX40L) positive cells among CD3+ splenocytes Reporter mRNA (Immune NP) 24 hours post-dose, transmembrane reporter


Slide 22

NHP in vivo Monocytes 22% of monocytes Buffer Control mRNA (Immune NP) Reporter (mOX40L) positive cells among CD3+ splenocytes 24 hours post-dose, transmembrane reporter


Slide 23

NHP in vivo Summary T cells B cells Monocytes 12% 13% 22% ~9 billion (109) ~1.5 billion (109) ~2 billion (109) Cell type Percentage (single dose) Est. whole body number* *Estimate for 70kg human and 5L blood volume; based on extrapolating observed NHP splenic cell percentage to whole body pool (by cell type) but excluding MALT for lymphoid cells 24 hours post-dose, transmembrane reporter Healthy CMV seropositive adults can have 5-10% of their peripheral CD8+ T cell pool responsive to the virus Human cell therapies (CART) dose ~300 million T-cells (~0.8% of CD8+) T regs (CD4+CD25+ FoxP3+) comprise 5–10% of CD4+T cells


Slide 24

Transient protein expression to reprogram cells into new functions and phenotypes Dose-dependent in vivo pharmacology to all major cell types (system) Leverage programable trafficking to ensure desired interactions mRNA software to select cell type(s) and ensure safety


Slide 25

mRNA as software mRNA software to select cell type(s) and ensure safety Specific microRNA signatures exist in different most cell lineages Targeting sequences can be used as logic-gates to ensure translation is limited to target cells


Slide 26

mRNA as software Jain, et al. MicroRNAs Enable mRNA Therapeutics to Selectively Program Cancer Cells to Self-Destruct. Nucleic Acid Therapeutics, 2018 Systemic delivery- IV injection miR3x122ts Caspase-6 3x122ts CTRL (no 122ts) 3x122ts CTRL (no 122ts) ALT 0 1500 3000 15000 30000 U/L 1500 3000 15000 30000 AST U/L 0


Slide 27

Software targeting miR TS Targeting sequence 1 (not disclosed) Purpose Effect “Express in T cells, not monocytes” Percent of transfection preserved, normalized to a miR-less version of the same reporter construct in the same cell type Targeting sequence 2 (not disclosed) “Express in monocytes, not T cells” Expression of transmembrane reporter in human PBMCs dosed with Immune NP (100 ng per 2E5 cells) by cell type miRless miRTS1 T cells Monocytes


Slide 28

Software targeting miR TS Targeting sequence 1 (not disclosed) Purpose Effect “Express in T cells, not monocytes” Percent of transfection preserved, normalized to a miR-less version of the same reporter construct in the same cell type Targeting sequence 2 (not disclosed) “Express in monocytes, not T cells” Expression of transmembrane reporter in human PBMCs dosed with Immune NP (100 ng per 2E5 cells) by cell type miRless miRTS1 T cells Monocytes


Slide 29

Software targeting miR TS Targeting sequence 1 (not disclosed) Purpose “Express in T cells, not monocytes” Percent of transfection preserved, normalized to a miR-less version of the same reporter construct in the same cell type Targeting sequence 2 (not disclosed) “Express in monocytes, not T cells” Expression of transmembrane reporter in human PBMCs dosed with Immune NP (100 ng per 2E5 cells) by cell type Effect


Slide 30

Software targeting miR TS Targeting sequence 1 (not disclosed) Purpose Effect “Express in T cells, not monocytes” Targeting sequence 2 (not disclosed) “Express in monocytes, not T cells”


Slide 31

Software targeting miR TS Targeting sequence 1 (not disclosed) Purpose “Express in T cells, not monocytes” Targeting sequence 2 (not disclosed) Illustrative protein “Express in monocytes, not T cells”


Slide 32

Software targeting Create novel and specific signaling between cells by leveraging both sides of the immune synapse


Slide 33

Transient protein expression to reprogram cells into new functions and phenotypes Dose-dependent in vivo pharmacology to all major cell types (system) Leverage programable trafficking to ensure desired interactions mRNA software to select cell type(s) and ensure safety


Slide 34

Putting it all together Transient protein expression to reprogram cells into new functions and phenotypes Dose-dependent in vivo pharmacology to all major cell types (system) mRNA software to select cell type(s) and ensure safety Can we achieve in vivo dose-dependent immune cell-based pharmacology leveraging multiple immune cells types*? *While avoiding off target liver expression with miR TS


Slide 35

Putting it all together Can we achieve in vivo dose-dependent immune cell-based pharmacology leveraging multiple immune cells types*? C57Bl/6 wild-type mice IV dose of immune NP every 2 days x 4 doses, containing either: non-translating (control) mRNA or CD19-CAR mRNA Monitor CD19+ cells in PBMC for activity, and harvest spleens at day 8 for full characterization *While avoiding off target liver expression with miR TS


Slide 36

Putting it all together This is not a CD19-CART, in fact expression will be on multiple cell types Expression with mRNA is transient and self-limiting CD19 is only used as a reporter to monitor activity against normal B cells (not diseased animals) T-cell Mac NK CD19 CD19 CD19


Slide 37

In vivo activity Targeted depletion of CD19+ cells * ** *** **** p<0.05 p<0.01 p<0.001 p<0.0001 T-test unpaired, 2-tailed 48h (1 dose) **** 96h (2 doses) 8 days (4 doses) * ns ** 76% 73% Cells in peripheral blood Cells in spleen (day 8 only) T cells (control) B cells (CD19+)


Slide 38

Immune summary Confidential and Proprietary ·  © 2019 Moderna Therapeutics


Slide 39

Transient protein expression to reprogram cells into new functions and phenotypes Dose-dependent in vivo pharmacology to all major cell types Leverage programable trafficking to ensure desired interactions mRNA software to select cell type(s) and ensure safety Putting it all together


Slide 40

Transient protein expression to reprogram cells into new functions and phenotypes Dose-dependent in vivo pharmacology to all major cell types Leverage programable trafficking to ensure desired interactions mRNA software to select cell type(s) and ensure safety Policeman mRNA-based immune system therapeutics


Slide 1

Why do we incorporate modified nucleotides into our mRNAs and are they really necessary? Confidential and Proprietary ·  © 2019 Moderna Therapeutics


Slide 2

Innate vs adaptive immunity Innate immunity (rapid response) Adaptive immunity (slow response) T cell Natural killer T cell Natural killer cell Macrophage Neutrophil Eosinophil Basophil (Primary white blood cell) CD8+ T cell CD4+ T cell Pathogen B cell Antibodies Dendritic cell Confidential and Proprietary ·  © 2019 Moderna Therapeutics


Slide 3

Sentinels of the Innate Immune System Toll-like Receptor (TLR) RIG-I Confidential and Proprietary ·  © 2019 Moderna Therapeutics


Slide 4

Confidential and Proprietary ·  © 2019 Moderna Therapeutics Dual consequences of triggering the innate immune system Translation Immune Signaling Ribosome Innate immune cell Low High Adaptive immune cell B cell


Slide 5

Confidential and Proprietary ·  © 2019 Moderna Therapeutics Uridine (U) is the critical nucleoside for TLR detection of ssRNA Toll-like Receptor (TLR)


Slide 6

Uridine (U) binding is critical for TLR8 homodimerization and activation Confidential and Proprietary ·  © 2019 Moderna Therapeutics Tanji … Shimizu (2015) Nat Struc Mol Biol


Slide 7

Uridine (U) base modifications are predicted to impair TLR8 homodimerization and activation 1-Methylpseudouridine (1mY) H N O O N Unmodified Uridine (U) H N O O HN Confidential and Proprietary ·  © 2019 Moderna Therapeutics


Slide 8

Systemic administration of U19 activates splenic B-cells, whereas 1mY19 does not C57BL6 mice IV administration 0.5 mg/kg Analyzed at 6 hrs. post-dose Activated B-cell Frequency Confidential and Proprietary ·  © 2019 Moderna Therapeutics B cell Antibodies IgG


Slide 9

Confidential and Proprietary ·  © 2019 Moderna Therapeutics C57BL6 mice IV administration 0.5 mg/kg Analyzed 6 hrs post-dose Genes regulated by innate immune stimulation PBS U19 1mY19 Systemic administration of U19 changes splenic gene expression profiles, whereas 1mY19 does not


Slide 10

Confidential and Proprietary ·  © 2019 Moderna Therapeutics dsRNA BOTTOM strand minor byproducts Transcription 1000's of copies TOP strand TOP strand BOTTOM strand DNA RNA polymerase What about mRNA? A, C, G, (U or 1mY)


Slide 11

Confidential and Proprietary ·  © 2019 Moderna Therapeutics Moderna's process for making mRNA results in very little dsRNA Highly sensitive assay for detecting dsRNA


Slide 12

Minimizing dsRNA substantially decreases innate immune activation, but… Confidential and Proprietary ·  © 2019 Moderna Therapeutics U 1mY19 Human Peripheral Blood Mononuclear Cells (PBMCs) Isolate Monocytes Differentiate to Macrophages Transfect with mRNA Measure IP-10 mRNA levels


Slide 13

… incorporating 1mY decreases it even more Confidential and Proprietary ·  © 2019 Moderna Therapeutics Human Peripheral Blood Mononuclear Cells (PBMCs) Isolate Monocytes Differentiate to Macrophages Transfect with mRNA Measure IP-10 mRNA levels U 1mY


Slide 14

Splenic B-cell activation demonstrates the advantage of both chemical & process optimization C57BL6 mice IV administration 0.5 mg/kg Analyzed at 6 hrs. post-dose Confidential and Proprietary ·  © 2019 Moderna Therapeutics B cell Antibodies IgG Activated B-cell Frequency 1mY19


Slide 15

Splenic B-cell activation demonstrates the advantage of both chemical & process optimization C57BL6 mice IV administration 0.5 mg/kg Analyzed at 6 hrs. post-dose Confidential and Proprietary ·  © 2019 Moderna Therapeutics B cell Antibodies IgG 1mY Activated B-cell Frequency Moderna process U 1mY19


Slide 16

Confidential and Proprietary ·  © 2019 Moderna Therapeutics C57BL6 mice IV administration 0.5 mg/kg Analyzed 6 hrs post-dose Genes regulated by innate immune stimulation PBS U Legacy U Moderna Almost no splenic gene expression changes upon systemic administration of 1mY Moderna mRNA 1mY19 Moderna


Slide 17

Effective mRNA therapeutics must avoid detection by innate immune sensors Global substitution of U with 1mY results in immune silent mRNA Moderna's synthesis process results in highly pure mRNA Summary Confidential and Proprietary ·  © 2019 Moderna Therapeutics


Slide 18

Confidential and Proprietary ·  © 2019 Moderna Therapeutics 5′ Cap Poly (A) tail Coding sequence 3′ UTR 5′ UTR Translation initiation fidelity Protein per unit time Functional mRNA half-life Desired mRNA features Desired cell type Tailored to protein type Start at the right place Faithful decoding Stop at the right place


Slide 19

Confidential and Proprietary ·  © 2019 Moderna Therapeutics Coding sequence engineering


Slide 20

Confidential and Proprietary ·  © 2019 Moderna Therapeutics Translation


Slide 21

Coding sequence length is dictated by the length of the encoded protein 0 500 1000 1500 2000 2500 3000 3500 4000 Length (nt) Moderna's experimental medicines 5′ Cap Poly (A) tail Coding sequence 3′ UTR 5′ UTR Confidential and Proprietary ·  © 2019 Moderna Therapeutics


Slide 22

Confidential and Proprietary ·  © 2019 Moderna Therapeutics Coding sequence engineering: discovering a needle in a haystack Amino acids: Lys Pro Thr Glu Asn Codons: AAG CCC ACC GAG AAC AAA CCU ACA GAA AAU CCA ACU CCG ACG Number of amino acids # of codon choices All valid! 2 4 4 2 2 * * * * = 128 choices Typical human protein (median length: 416 aa):   Estimated number of atoms in known universe:   www.universetoday.com/36302/atoms-in-the-universe/


Slide 23

Confidential and Proprietary ·  © 2019 Moderna Therapeutics How does one choose a CDS? Randomly choose synonymous codons? Weight synonymous codon choice by use frequencies in human mRNAs? Use only the 20 most "optimal" human codons? What about secondary structure? Should we minimize, maximize, or something in between? 5′ Cap Poly (A) tail Coding sequence 3′ UTR 5′ UTR


Slide 24

Confidential and Proprietary ·  © 2019 Moderna Therapeutics Codon optimality tRNAs compete with each other for binding. The more abundant the tRNA – the more optimal the codon. Fast: Optimal codons Sub-optimal codons Slow:


Slide 25

Many ribosomes per mRNA = Polysome Modified from Kiseleva (1989) FEBS Letters Confidential and Proprietary ·  © 2019 Moderna Therapeutics


Slide 26

Ribosome collisions lead to ribosome traffic jams Slow codons Polysome Ribosome traffic pileup mRNA cleavage Cleaved mRNA Fast codons Structure of two collided ribosomes Ikeuchi … Inada EMBO J 2019 Confidential and Proprietary ·  © 2019 Moderna Therapeutics


Slide 27

Confidential and Proprietary ·  © 2019 Moderna Therapeutics 5′ Cap Poly (A) tail Coding sequence 3′ UTR 5′ UTR Another key feature of mRNA is its secondary structure Backbone Bases


Slide 28

What's the right balance to maximize protein output? Slower translation Faster translation mRNA secondary structure Strong secondary structure Weak secondary structure Codon optimality Low tRNA concentration High tRNA concentration after Gorochowski…Roubos (2014) NAR fast slow Confidential and Proprietary ·  © 2019 Moderna Therapeutics


Slide 29

Codon optimality and secondary structure strength can be calculated Codon optimality Folding energy (DG) -297 kcal/mol -370 kcal/mol -463 kcal/mol Confidential and Proprietary ·  © 2019 Moderna Therapeutics low structure high structure med structure Slow Optimal


Slide 30

Confidential and Proprietary ·  © 2019 Moderna Therapeutics Relative Synonymous Codon Usage (RSCU) 0.5 0.6 0.7 0.8 0.9 1.0 -250 -300 -350 -400 -450 -500 Folding Energy (DG) Random codon choice Human genome weighted choice Moderna algorithm Optimal Slow Low Structure High Structure eGFPd coding sequence Computational design allows exploration of the limits of codon optimality vs structure


Slide 31

Confidential and Proprietary ·  © 2019 Moderna Therapeutics GFPd1 mRNA GFP Nuclei 72 h time-lapse, HeLa GFPd1 degron tag Short-lived GFP allows us to follow translation and mRNA decay kinetics in cells


Slide 32

Confidential and Proprietary ·  © 2019 Moderna Therapeutics Different coding sequences display different expression kinetics GFPd1 mRNA GFPd2 mRNA GFP Nuclei 72 h time-lapse, HeLa eGFPd2 degron tag GFPd1 degron tag


Slide 33

AUC Confidential and Proprietary ·  © 2019 Moderna Therapeutics The initial rate of translation is not a good predicter of overall eGFP expression, … R = 0.45 Relative AUC Rate of translation (kTrans)


Slide 34

AUC Confidential and Proprietary ·  © 2019 Moderna Therapeutics … but overall eGFP expression strongly correlates with functional mRNA half-life Relative AUC


Slide 35

AUC Confidential and Proprietary ·  © 2019 Moderna Therapeutics Both codon optimality and CDS structure positively impact functional mRNA half-life


Slide 36

AUC Optimizing codons and maximizing coding sequence structure can increase total protein production by >10-fold Relative AUC Structure Codons Slow Total protein Confidential and Proprietary ·  © 2019 Moderna Therapeutics


Slide 37

We used computational design to thoroughly explore the relationship between codon optimality and mRNA secondary structure. Mauger … MacFadyen (2019) BioRxiv 549022 We now have a new tool for dialing in desired protein output Confidential and Proprietary ·  © 2019 Moderna Therapeutics Summary


Slide 38

Confidential and Proprietary ·  © 2019 Moderna Therapeutics 5′ Cap Poly (A) tail 3′ UTR AUG 5′ UTR UAA UAG UGA Start at the right place Faithful decoding Stop at the right place Coding sequence Translation initiation fidelity Protein per unit time Functional mRNA half-life Desired mRNA features Desired cell type Tailored to protein type


Slide 39

Confidential and Proprietary ·  © 2019 Moderna Therapeutics 5′ Cap Poly (A) tail AUG UAA UAG UGA Start at the right place Faithful decoding Stop at the right place Coding sequence 3′ UTR 5′ UTR Translation initiation fidelity Protein per unit time Functional mRNA half-life Desired mRNA features Desired cell type Tailored to protein type


Slide 40

Confidential and Proprietary ·  © 2019 Moderna Therapeutics UTRs contain key regulatory information 5′ Cap Poly (A) tail Coding sequence 3′ UTR AUG 5′ UTR UAA UAG UGA Start at the right place Faithful decoding Stop at the right place Controls speed at which ribosomes load in different cell types & under different conditions Ribosome “on ramp” Controls mRNA half-life & subcellular localization Regulatory protein RISC miRNA mRNA decay Translation Protein complex that interacts with Kinesin mRNA Kinesin Microtubule


Slide 41

Confidential and Proprietary ·  © 2019 Moderna Therapeutics UTR optimization


Slide 42

Confidential and Proprietary ·  © 2019 Moderna Therapeutics Power of sequence engineering …Can we do better? mRNA expression 5′ Cap Poly (A) tail Coding sequence 3′ UTR AUG 5′ UTR UAA UAG UGA Start at the right place Faithful decoding Stop at the right place Moderna mRNA sequence: Optimized coding sequence flanked by Moderna’s 5′ & 3′ UTR sequences


Slide 43

Translation initiation mRNA 1 Small subunit recruitment Coding sequence 3′ UTR 5′ UTR AUG 5′ Cap Poly (A) tail Confidential and Proprietary ·  © 2019 Moderna Therapeutics


Slide 44

Translation initiation mRNA 1 Small subunit recruitment 2 Start codon recognition and large subunit recruitment Coding sequence 3′ UTR 5′ UTR AUG 5′ Cap Poly (A) tail Confidential and Proprietary ·  © 2019 Moderna Therapeutics


Slide 45

Translation initiation mRNA 1 Small subunit recruitment 3 Translation and elongation 2 Start codon recognition and large subunit recruitment Coding sequence 3′ UTR 5′ UTR AUG 5′ Cap Poly (A) tail Confidential and Proprietary ·  © 2019 Moderna Therapeutics


Slide 46

Translation initiation mRNA 1 Small subunit recruitment 3 Translation and elongation 4 Termination Functional protein 2 Start codon recognition and large subunit recruitment Coding sequence 3′ UTR 5′ UTR AUG 5′ Cap Poly (A) tail Confidential and Proprietary ·  © 2019 Moderna Therapeutics


Slide 47

Coding sequence 3′ UTR 5′ UTR Transfect mRNA library ~300,000 Neural Network Using neural networks to develop 5′ UTRs with high ribosome loading Polysome profiling ribosome load Ribosome load random human evolved Collaboration with Seelig lab, University of Washington Sample et al. bioRxiv doi: 10.1101/310375 in press Nature Biotech 2019 Evolved 5´ UTR Confidential and Proprietary ·  © 2019 Moderna Therapeutics


Slide 48

Translation initiation 1 Small subunit recruitment mRNA Leaky scanning Coding sequence 3′ UTR 5′ UTR AUG 5′ Cap Poly (A) tail AUG Confidential and Proprietary ·  © 2019 Moderna Therapeutics


Slide 49

Translation initiation Coding sequence 3′ UTR 5′ UTR AUG 5′ Cap Poly (A) tail AUG 1 Small subunit recruitment mRNA 3 Start codon recognition and large subunit recruitment 2 Start codon missed Leaky scanning Confidential and Proprietary ·  © 2019 Moderna Therapeutics


Slide 50

Translation initiation Coding sequence 3′ UTR 5′ UTR AUG 5′ Cap Poly (A) tail AUG 1 Small subunit recruitment mRNA 3 Start codon recognition and large subunit recruitment 4 Translation & elongation 2 Start codon missed Leaky scanning Confidential and Proprietary ·  © 2019 Moderna Therapeutics


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Truncated protein Translation initiation Coding sequence 3′ UTR 5′ UTR AUG 5′ Cap Poly (A) tail AUG 1 Small subunit recruitment mRNA 3 Start codon recognition and large subunit recruitment 4 Translation & elongation 5 Termination 2 Start codon missed Leaky scanning Confidential and Proprietary ·  © 2019 Moderna Therapeutics


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Designing 5′ UTRs with desired features Random library 2 x 109 5′ UTRs 5′ UTR lead sequences In vitro analysis of sequences and identification of lead candidates In vivo validation of lead candidates in rodents Disease-relevant animal model Confidential and Proprietary ·  © 2019 Moderna Therapeutics High translation initiation fidelity Rational design 5′ UTR library 5′ Cap Poly (A) tail Coding sequence 3′ UTR 5′ UTR


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5′ UTR screening: protein expression vs. initiation fidelity Confidential and Proprietary ·  © 2019 Moderna Therapeutics 5′ Cap Poly (A) tail Coding sequence 3′ UTR 5′ UTR Initiation fidelity Expression HeLa (human cancer cells) AML12 (mouse liver cells) log2 transformed New 5′ UTRs with HIGH expression and HIGH initiation fidelity Initiation fidelity Expression Standard Standard


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3′ UTR optimization can increase mRNA potency 5′ Cap Poly (A) tail Coding sequence 3′ UTR AUG 5′ UTR UAA UAG UGA Start at the right place Faithful decoding Stop at the right place Confidential and Proprietary ·  © 2019 Moderna Therapeutics


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3′ UTR leads shows higher potency HeLa mouse hepatocytes …what does this mean for our future medicines? mRNA expression Confidential and Proprietary ·  © 2019 Moderna Therapeutics


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3′ UTR lead in disease mouse model 1 Confidential and Proprietary ·  © 2019 Moderna Therapeutics 7 14 Day 0 Day 15 15 Protein -3 Biomarker -2 0 2 4 6 0 40 80 120 160 Days % Control biomarker 1 -3 Biomarker Editable Prism Graph Control Moderna standard sequence Moderna improved sequence


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Confidential and Proprietary ·  © 2019 Moderna Therapeutics RNA Protein Activity Day 32 16 21 23 25 28 32 Day 7 14 0 5′/3′ UTR lead combination in disease model 2


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0 7 14 21 28 80 90 100 110 120 Days post Injection % Change in body weight Confidential and Proprietary ·  © 2019 Moderna Therapeutics Body weight Biomarker Body weight Biomarker 16 21 23 25 28 32 Day 7 14 0 Editable Prism Graph 5′/3′ UTR lead combination in disease model 2 Control Moderna standard sequence Moderna improved sequence


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UTR optimization enables increased potency & duration of efficacy 5′ Cap Poly (A) tail Coding sequence 3′ UTR AUG 5′ UTR UAA UAG UGA Start at the right place Faithful decoding Stop at the right place Translation initiation fidelity Protein per unit time Functional mRNA half-life Increased mRNA potency Reduced dosing frequency Confidential and Proprietary ·  © 2019 Moderna Therapeutics


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We target different tissues via multiple routes of administration (ROAs) Confidential and Proprietary ·  © 2019 Moderna Therapeutics


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Most ROAs require mRNA encapsulation: Lipid Nanoparticles (LNPs) PEG lipid Ionizable lipid Cholesterol Phospholipid mRNA Different LNPs for different delivery goals: Enhanced IV delivery to liver allows repeat dosing for treatment of rare diseases Enhanced IM delivery for vaccines Sabnis … Benenato (2018) Molecular Therapy Hassett … Brito (2019) Mol Ther Nuc Acids Confidential and Proprietary ·  © 2019 Moderna Therapeutics


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How do we enable rational structure-based design for LNPs? components function structure Δ molecules Δ composition Δ process Chemical stability Physical stability Biodistribution Cellular uptake Endosomal escape Protein expression Confidential and Proprietary ·  © 2019 Moderna Therapeutics


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How are we tackling LNP structure? Cryogenic Electron Microscopy (CryoEM) Physics! Nuclear Magnetic Resonance (NMR) Atomic Force Microscopy (AFM) Small-Angle X-ray Scattering (SAXS) Small-Angle Neutron Scattering (SANS) Confidential and Proprietary ·  © 2019 Moderna Therapeutics


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How do we enable rational structure-based design for LNPs? components function structure Δ molecules Δ composition Δ process Chemical stability Physical stability Biodistribution Cellular uptake Endosomal escape Protein expression Confidential and Proprietary ·  © 2019 Moderna Therapeutics


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structure function Chemical stability Physical stability Biodistribution Cellular uptake Endosomal escape Protein expression How can we elucidate the assembly process? components Δ molecules Δ composition Δ process Confidential and Proprietary ·  © 2019 Moderna Therapeutics black box


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Confidential and Proprietary ·  © 2019 Moderna Therapeutics Watching LNP assembly in real time


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Confidential and Proprietary ·  © 2019 Moderna Therapeutics LNP assembly 1x10-12 1x10-11 1x10-10 1x10-9 1x10-9 1x10-8 1x10-7 1x10-6 1x10-5 1x10-4 1x10-3 1x10-2 1x10-1 1x100 1x101 1x102 1x10-3 1 second 1 minute 1 hour 1x10-12 1x10-11 1x10-10 1x10-9 1x10-8 1x10-7 1x10-6 1x10-5 0.0001 0.001 0.01 0.1 1 10 100 1000 black box


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Confidential and Proprietary ·  © 2019 Moderna Therapeutics LNP assembly via coarse-grained molecular dynamics


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Confidential and Proprietary ·  © 2019 Moderna Therapeutics Molecular modeling Volpon … Borden (2006) EMBO


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Central Dogma of Molecular Modeling “The fundamental laws necessary for the mathematical treatment of the whole of chemistry are thus completely known, and the difficulty lies only in the fact that application of these laws leads to equations that are too complex to be solved.” Time-dependent Schrödinger equation - Paul Dirac, 1905 Confidential and Proprietary ·  © 2019 Moderna Therapeutics


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Confidential and Proprietary ·  © 2019 Moderna Therapeutics Molecular modeling 5 nm 80 nm to scale ~ 2-6 mRNA molecules of each component ~ 6k phospholipid ~ 30k ionizable lipid ~ 20k cholesterol ~ 1k PEG lipid


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Confidential and Proprietary ·  © 2019 Moderna Therapeutics Molecular simulations Adapted from Perilla … Schulten (2013) Curr. Opin. Struct. Biol. 1Å 1nm 10nm 100nm 1µm Quantum mechanical simulations All-atom molecular dynamics Lipids mRNA Proteins Small molecules Atoms


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Confidential and Proprietary ·  © 2019 Moderna Therapeutics Molecular simulations Adapted from Perilla … Schulten (2013) Curr. Opin. Struct. Biol. 1Å 1nm 10nm 100nm 1µm Quantum mechanical simulations All-atom molecular dynamics Lipids mRNA Proteins Small molecules Atoms Small organelles Bacterium Virus capsids


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Confidential and Proprietary ·  © 2019 Moderna Therapeutics Molecular simulations Adapted from Perilla … Schulten (2013) Curr. Opin. Struct. Biol. 1Å 1nm 10nm 100nm 1µm Quantum mechanical simulations All-atom molecular dynamics Virus capsids Lipids mRNA Proteins Small molecules Atoms Small organelles Bacterium


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Confidential and Proprietary ·  © 2019 Moderna Therapeutics Molecular simulations Adapted from Perilla … Schulten (2013) Curr. Opin. Struct. Biol. 1Å 1nm 10nm 100nm 1µm Quantum mechanical simulations All-atom molecular dynamics Lipid nanoparticles Lipids mRNA Proteins Small molecules Atoms Small organelles Bacterium


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Confidential and Proprietary ·  © 2019 Moderna Therapeutics Molecular simulations Adapted from Perilla … Schulten (2013) Curr. Opin. Struct. Biol. Lipid nanoparticles Lipids mRNA 1Å 1nm 10nm 100nm 1µm Quantum mechanical simulations All-atom molecular dynamics Coarse-grained molecular dynamics Proteins Small molecules Atoms Small organelles Bacterium


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Coarse-grained modeling igem.org “all-atom” representation Confidential and Proprietary ·  © 2019 Moderna Therapeutics


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Coarse-grained modeling igem.org “coarse-grain” representation “all-atom” representation Confidential and Proprietary ·  © 2019 Moderna Therapeutics


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Confidential and Proprietary ·  © 2019 Moderna Therapeutics Coarse-grained modeling Risselada … Grubmüller (2014) PNAS Pinot … Barelli (2014) Science Barneda … Christian (2015) eLife


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Confidential and Proprietary ·  © 2019 Moderna Therapeutics LNP components 6 µs 700 hours Proto LNP ~ 2-6 mRNA Components ~ 6k phospholipid ~ 30k ionizable lipid ~ 20k cholesterol ~ 1k PEG lipid 15 nm


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Confidential and Proprietary ·  © 2019 Moderna Therapeutics Simulation of “proto LNP” assembly cholesterol: head tail phospholipid: head tail ionizable lipid: head tail RNA oligomer: backbone nucleoside 25 nm 5.6 µs 5.4 µs 1.3 µs 1 µs 300 ns 5 nm 10 nm 15-35 nm


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Simulation of RNA encapsulation 1.3 µs 1 µs cholesterol: head tail phospholipid: head tail ionizable lipid: head tail RNA oligomer: backbone nucleoside 15 nm Confidential and Proprietary ·  © 2019 Moderna Therapeutics


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Simulation of RNA encapsulation 1.3 µs 1 µs cholesterol: head tail phospholipid: head tail ionizable lipid: head tail RNA oligomer: backbone nucleoside 15 nm Confidential and Proprietary ·  © 2019 Moderna Therapeutics


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Confidential and Proprietary ·  © 2019 Moderna Therapeutics LNP assembly 1 second 1 minute 1 hour 1x10-12 1x10-11 1x10-10 1x10-9 1x10-9 1x10-8 1x10-7 1x10-6 1x10-5 1x10-4 1x10-3 1x10-2 1x10-1 1x100 1x101 1x102 1x10-3 1x10-12 1x10-11 1x10-10 1x10-9 1x10-8 1x10-7 1x10-6 1x10-5 0.0001 0.001 0.01 0.1 1 10 100 1000


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How do we enable rational structure-based design for LNPs? components function structure Δ chemistry Δ composition Δ process Chemical stability Physical stability Biodistribution Cellular uptake Endosomal escape Protein expression Confidential and Proprietary ·  © 2019 Moderna Therapeutics


LOGO

Expressing RALDH in skin-draining lymph nodes Skin Skindraining LN Vaccination Reporter Protein (mCitrine) T cells (CD3) Wait 24h 1.18 0.86 1.26 Reporter Protein CD45 B cells T cells Control modRNA


LOGO

Ethanol Am80 Small intestine 7 days post vaccination RALDH mRNA immune NP Peripheral vaccination with immune NP containing RALDH mRNA induces mucosal memory cells Spleen IEL LPL 102 103 104 105 106 107 Total OT-I recovered ETOH AM80 RALDH+retinal Vaccine only Vaccine + AM80 Vaccine + RALDH mRNA immune NPs Small intestine IEL LPL

EX-99.2

Slide 1

Norwood May 2019 DNA mRNA Protein Exhibit 99.2


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This presentation contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995, as amended including, but not limited to, statements concerning: mRNA as a potential new class of medicines; the scope of the mRNA opportunity; Moderna’s ability to scale its manufacturing over time; the ability of Moderna’s Norwood manufacturing facility to support Phase 2, Phase 3, and commercial activities; Moderna’s ability to reduce its manufacturing costs in the future; and Moderna’s projected manufacturing capability and costs. In some cases, forward-looking statements can be identified by terminology such as “will,” “may,” “should,” “expects,” “intends,” “plans,” “aims,” “anticipates,” “beliefs,” “estimates,” “predicts,” “potential,” “continue,” or the negative of these terms or other comparable terminology, although not all forward-looking statements contain these words. The forward-looking statements in this presentation are neither promises nor guarantees, and you should not place undue reliance on these forward-looking statements because they involve known and unknown risks, uncertainties and other factors, many of which are beyond Moderna’s control and which could cause actual results to differ materially from those expressed or implied by these forward-looking statements. These risks, uncertainties and other factors include, among others, those described under the heading “Risk Factors” in Moderna’s most recent Annual Report on Form 10-K filed with the U.S. Securities and Exchange Commission (SEC) and in subsequent filings made by Moderna with the SEC, which are available on the SEC's website at www.sec.gov. Except as required by law, Moderna disclaims any intention or responsibility for updating or revising any forward-looking statements in this presentation in the event of new information, future developments or otherwise. These forward-looking statements are based on Moderna’s current expectations and speak only as of the date hereof. Forward-looking statements


Slide 3

Moderna Mission & Role of Norwood Stéphane Bancel DNA mRNA Protein


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Large product opportunity Higher probability of technical success Accelerated research and development timelines Greater capital efficiency over time vs. recombinant technology mRNA as a potential new class of medicines


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Moderna’s Mission Deliver on the promise of mRNA science to create a new generation of transformative medicines for patients.


Slide 6

Norwood Vision: To enable Moderna scale up for the next 20 years Fully integrated site: Raw materials + API + Formulation + Fill vials + Finish + Ship to clinical sites + QC Highly flexible Highly scalable: Up to 100 GMP batches of mRNA planned per year Fully digital site Environmentally friendly Focusing on: Quality » Scalability » Speed » Cost


Slide 7

GMP manufacturing strategy: Phase appropriate Norwood now provides the scalability we need for our growing pipeline 2011 - 2013 2014 - 2015 2016 - 2018 2H 2018+ Plasmid: No GMP needs • Outsourced • Outsourced • Norwood mRNA: • • Moderna, Cambridge • Outsourced • Norwood Form: • • Moderna, Cambridge • Outsourced • Norwood Fill: • • • Norwood Finish: • • Outsourced • Norwood QC: • • Outsourced • Norwood Sourced entirely by CMOs Sourced by CMOs + 200TS Norwood is primary, with CMO network as backup Outsourced Outsourced Outsourced Outsourced Outsourced Outsourced


Slide 8

Norwood: 3 businesses in 1 plant Core business: GMP manufacturing to supply our clinical pipeline Preclinical Production for Research Engine (was in Cambridge, moved to NW to reduce real estate cost) Personalized Cancer Vaccine (PCV)


Slide 9

Manufacturing Capability Juan Andres DNA mRNA Protein


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What we do… Create Make


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What we do… Create Technical Development


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Technical development enabled scale 2015 < 20 employees Scale for mRNA content in final Drug Product (DP) ~2.5g ~2 GLP toxicology/consistency batches (DP) completed >150 in 2019, 30% PhDs Scale for mRNA content in final Drug Product (DP) ~10g with line of sight to 100g within next 12 month >60 GLP toxicology/consistency batches (DP) completed between 2015 and today Current


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Technical development enabled scale 2015 < 20 employees Scale for mRNA content in final Drug Product (DP) ~2.5g ~2 GLP toxicology/consistency batches (DP) completed >150 in 2019, 30% PhDs Scale for mRNA content in final Drug Product (DP) ~10g with line of sight to 100g within next 12 month >60 GLP toxicology/consistency batches (DP) completed between 2015 and today Current


Slide 14

What we do… Make Internal & External GMP Manufacturing Pre-Clinical


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We make bold choices: Norwood


Slide 16

Manufacturing asset as competitive advantage to effective industrialization of a platform technology Cost at economical scale – progressing as planned Enables fast scale up Competitive Advantage of mRNA technology Critical mass in production volume Less future capital investment Process improvements translating fast to platform processes No live cells, body act as bioreactor


Slide 17

Pre-clinical automation enabled speed of research 2014 Manual mRNA production process Time from order to mRNA delivery ~120 days Located in Cambridge Fully automated mRNA production process Time from order to mRNA delivery ~30-45 days Located in Moderna Manufacturing Site, Norwood Current


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Pre-clinical automation enabled speed of research 2014 Manual mRNA production process Time from order to mRNA delivery ~120 days Located in Cambridge Fully automated mRNA production process Time from order to mRNA delivery ~30-45 days Located in Moderna Manufacturing Site, Norwood Current


Slide 19

Built internal GMP Production Capability early in the lifecycle 2015 No internal GMP Production, DS and DP outsourced to CMOs 2 GMP clinical trial mRNA vaccine batches (DS+DP) completed Internal GMP DS and DP production since April 2016 Advanced from 10g output in 2016 to 45g DS output in 2018 ~50 GMP clinical trial batches (DS+DP) for various indications completed as of YE 2018 Current


Slide 20

Built internal GMP Production Capability early in the lifecycle 2015 No internal GMP Production, DS and DP outsourced to CMOs 2 GMP clinical trial mRNA vaccine batches (DS+DP) completed Internal GMP DS and DP production since April 2016 Advanced from 10g output in 2016 to 45g DS output in 2018 ~50 GMP clinical trial batches (DS+DP) for various indications completed as of YE 2018 Current


Slide 21

Norwood equipped to support Phase III & initial launch Norwood equipped to become Phase III and initial launch site and support demand for upside scenarios for some processes/products Optionality enabled with US based CMO that has a longstanding experience with commercial Drug Product Production Additional commercial Manufacturing Sites investment decision can be deferred Outsourcing non-core to mRNA activities like commercial Fill & Finish will further mitigate additional investment


Slide 22

As we scale and streamline the process… Scale progression 2015/2016 2017/2018 2020/2022 When commercial & at scale 2.5g 10g 100g >500g


Slide 23

…Cost is rapidly improving. 2015/2016 2017/2018/2019 2020/2022 Scale progression Direct Drug Substance Cost ($/mg) 45-55% When commercial & at scale 2015/2016 to 2017/2018/2019 drug substance costs reductions are based upon illustrative examples for different development candidates


Slide 24

Manufacturing is becoming a competitive advantage Critical mass of platform approach enables accelerated learning and rapid adoption of technical advances End to End integration of different technologies (Plasmid; Drug Substance; Drug Product) at Norwood creates Flexibility = â cost á speed Top CMC Talent (recruit & retain) is driven by Moderna’s mission, science & speed